With the advent of the aging society and for improved compliance of patients, the significance of orally disintegrating tablets which can be taken without water has been emphasized in recent years. As conventional orally disintegrating tablets, those produced by lyophilizing with substances such as gelatin and the like in a container, those obtained by wet-tableting wet powder or granulated particles, and the like are known. However, such tablets are sometimes cracked or chipped during transport, do not entirely have sufficient hardness, and also require complicated production methods.
Furthermore, even if conventional orally disintegrating tablets have good tablet hardness immediately after production, their hardness will be likely to decrease during storage because of moisture absorption, so they will be cracked or chipped when pushing out of PTP sheet. Various attempts have been made to solve these defects and, for example, the following techniques have been proposed in the documents.
Patent document 1 discloses that an orally disintegrating compressed molding shows quick disintegration and dissolution in the oral cavity, which comprises a difficultly moldable saccharide and a readily moldable saccharide. However, production of the orally disintegrating tablet described in the document essentially requires humidification and drying steps after tableting at low pressure, which necessitates a large number of production steps and cumbersome operations. Moreover, even though a certain level of hardness is achieved immediately after production, the problem of decreased hardness due to moisture absorption during storage remains unsolved.
Patent document 2 discloses that a tablet comprising a sugar alcohol or a saccharide with an average particle diameter of not more than 30 μm, an active ingredient, and a disintegrant, has shown good tablet hardness immediately after production. However, it does not describe whether the hardness can also be maintained during storage.
Patent document 3 discloses an orally disintegrating, molded composition which easily disintegrates in an oral cavity, containing organic acid(s), carbonate(s), network maintaining agent(s), and color-change preventing agent(s), wherein a network is formed among said organic acid(s) said carbonate(s), said network maintaining agent(s) and said color-change preventing agent(s), wherein said network maintaining agent is at least one water insoluble solid material selected from a group composed of corn starch, potato starch, sodium carboxymethyl starch, crystalline cellulose, low substituted hydroxypropylcellulose, and croscarmellose sodium, wherein said color-change preventing agent is at least one water soluble sugar selected from a group composed of erythritol, xylitol, mannitol, and lactose, and herein 25.0-625.0 weight part of said network maintaining agent and 25.0-937.5 weight part of said color-change preventing agent are formulated for 100 weight part of a mixture of said organic acid and said carbonate. However, since the tablets require removal of carbon dioxide gas and water therefrom by heating the tablet after tableting, special production facility and technique are necessary, and the operation is also cumbersome. Moreover, it is impossible to apply the technique of this document to active ingredients unstable to temperature and water.
Patent document 4 discloses a rapidly disintegrable solid preparation which comprises 1) a pharmacologically active ingredient, 2) a sugar and 3) a low substituted hydroxypropylcellulose having 5 wt % or more to less than 7 wt % of hydroxypropoxyl group. However, since the low substituted hydroxypropylcellulose used in the document is not commercially available, it is not entirely widely available.
Patent document 5 discloses a tablet which comprises a starch, a water-soluble excipient and a medicament and substantially not containing a binder other than starch, patent document 6 discloses a quickly disintegrating solid preparation comprising a) an active ingredient, b) a saccharide or sugar alcohol with the average particle diameter of 30 μm to 300 μm, c) a disintegrating agent, and d) a cellulose compound, and patent document 7 discloses an orally disintegrating composition, which is a molded composition rapidly disintegrated in an oral cavity, and comprising a filler comprised of sugar alcohol, a disintegrating agent and a lubricant, wherein the penetration rate of ethanol into this lubricant is 3.0×10−3 g2/sec or above. In any documents, the hardness is not sufficient for practical use since the tablet with the tablet hardness described therein may be cracked or chipped. In addition, the documents do not describe hardness and stability of the tablets during storage.
Patent document 8 discloses an intraorally rapidly disintegrating tablet, which comprises D-mannitol having an average particle diameter of 31 μm to 80 μm, an active ingredient, a disintegrant, and stearic acid or a metallic stearate in an amount of 0.01 wt % to 0.5 wt %. However, a special facility of an external lubrication system is essential.
Therefore, in the prior art, an orally disintegrating tablet having practically sufficient tablet hardness and storage stability, which can be produced using usually available pharmaceutical manufacturing apparatuses and machines and according to convenient method, is not known.
patent document 1: WO 95/20380
patent document 2: WO 97/47287
patent document 3: JP-A-11-310539
patent document 4: JP-A-2000-103731
patent document 5: WO 00/47233
patent document 6: JP-A-2001-58944
patent document 7: WO 2001/076565
patent document 8: WO 2003/103713